Opioid formulations

ABSTRACT

The present invention provides high-concentration formulations of opioids such as fentanyl or fentanyl congeners. The formulation of the invention comprises fentanyl or a fentanyl congener in concentrations significantly in excess of conventional formulations, e.g., on the order about 2-fold to about 10,000-fold greater than conventional formulations, e.g., currently commercially available formulations. These formulations are particularly useful for long-term delivery to a subject suffering from pain. The invention further provides drug delivery devices comprising the high-concentration opioid formulations, and further provides methods of alleviating pain in a subject, comprising administering the high-concentration formulations to a subject in need thereof.

FIELD OF THE INVENTION

[0001] The invention relates to high-concentration formulations ofopioids to alleviate pain.

BACKGROUND OF THE INVENTION

[0002] Opiates in various forms, including opium, heroine and morphinewhich derive from the opium poppy, have very powerful analgesicproperties and have seen widespread use for anesthesia as well thetreatment of pain, especially where the pain is very severe. In additionto these natural opiates, many synthetic opioids have since beensynthesized including fentanyl and congeners of fentanyl such assufentanil, alfentanil, lofentanil, carfentanil, remifentanil, etc.,which are many times more potent than morphine.

[0003] At present, the dosage form with the most widespread use is stillmorphine administered orally, although opioids can also be delivered byintravenous infusion (see, e.g., Scholz et al. 1996 Clin. Pharmacokinet.31:275-92; White 1989 Anesth. Analg. 68:161-71), oral administration,(see, e.g., U.S. Pat. Nos. 4,769,372; 5,202,128; and 5,378,474),epidural or intrathecal administration (see, e.g., Vercauteren et al.1998 Anaesthesia 53:1022-7; Stephens 1997 Am. Fam. Physician 56:463-70),transdermal application (e.g., using a transdermal patch (see, e.g.,U.S. Pat. No. 4,588,580)), or subcutaneous injection (see, e.g., Paix etal. 1995 Pain 63:263-9; Bruera et al. 1988 Cancer 62:407-11; Moulin etal. 1992 Can. Med. Assoc. J. 146:891-7). For a review, see, e.g., Clotzet al. 1991 Clin. Pharm. 10:581-93; and Anderson et al. 1998 J. Pharm.Care Pain Symptom Control 6:5-21.

[0004] Unfortunately, oral administration of morphine meets with severaldisadvantages. Many extremely ill patients can no longer take drugsorally for a variety of reasons, such as the inability to swallow orgastrointestinal obstruction. Furthermore, long-term oral administrationoften necessitates the ingestion of multiple pills or tablets many timesa day, a dosing scheme commonly associated with poor compliance. Forthese and other reasons, parenteral administration of opioids can be apreferred alternative to oral administration.

[0005] However, parenteral administration of opioids meets with severalchallenges. Many patients, especially those with chronic-pain ordiseases, require long-term treatment with opioids, e.g., for days,months, years and sometimes for the lifetime of the patient, andtherefore require large quantities of drug to be administered over time.Also, many patients with severe pain require high doses of opioids tocontrol pain, oftentimes with escalating requirements due to progressionof the underlying disease state or development of tolerance to theopioid. Furthermore, in order to provide convenient, long-term orhigh-dosage pain treatment, opioids may need to be infused continuouslyand for long duration, usually by means of an infusion pump which can bean implantable or external pump. In order to provide acceptableconvenience and mobility to patients, infusion pumps must be limited insize which in turn limits the volume of drug formulation that can becontained within. When opioids are administered for long durations usingconventional formulations of opioids, the limited size of the drugreservoir of the pumps requires such pumps to be frequently refilled orexchanged which, besides being inconvenient, also requires the attentionof a skilled health care worker and exposes the patient to possibleinfection.

[0006] Besides limitations imposed by pump size, the absorption capacityof the tissue into which the drug formulation is infused can limit theamount of volume of drug formulation that can be absorbed. For example,the absorptive capacity of the subcutaneous tissue is generally amaximum of 10 ml per hour (see e.g., Anderson et al., supra).Furthermore, infusions of large amounts of fluid into certain tissue cancause tissue edema which causes discomfort to the patient.

[0007] Currently available opioid formulations are too dilute to meetthe needs of patients requiring long term treatment or large drug dosesto control pain. For example, sufentanil citrate is currently availablein an aqueous solution at a concentration of 50 μg/mL; morphine at 1mg/mL; morphine sulfate at 20 mg/mL; fentanyl citrate at 20 μg/ml andalfentanil at 500 μg/mL. Simply adding more drug to conventional aqueousformulations is not a viable solution to creating more concentratedformulations as the opioid compound, especially those which arelipophilic such as fentanyl and its congeners, may precipitate out ofsolution which leads to, for example inconsistent delivery rates,reduced drug absorption, reduced tissue response and clogging of thedrug delivery device or other points along the infusion pathway.

[0008] For the foregoing discussion, it is evident that there is a needin the art for more concentrated opioid formulations that permitconvenient long-term or high dose delivery yet is stable over time andsafe for parenteral use. The present invention addresses this need, andprovides related advantages as well.

SUMMARY OF THE INVENTION

[0009] The present invention provides opioid formulations suitable forlong-term delivery to a subject. The formulation of the inventioncomprises fentanyl or a fentanyl congener, and a solvent in which thefentanyl or fentanyl congener can be provided in concentrationssignificantly in excess of conventional formulations, e.g., on the orderabout 2-fold to about 10,000-fold greater than conventionalformulations, e.g., currently commercially available formulations. Inthe present invention, concentrated opioid formulations useful forparenteral delivery are created by solubilizing in non-aqueous solutionsextremely potent opioid compounds, e.g., fentanyl and its congeners,which are hundreds to thousands of times more potent than morphine. Theformulations of the invention are especially useful for high-dosedelivery, or long-term delivery, e.g., several hours, weeks, months, oreven years. Long-term delivery can be achieved using various external orimplanted devices.

[0010] The invention further provides a sustained release dosage formcomprising a formulation of the invention. The dosage form can be anexternal, partially implanted, or implanted device (e.g., biodegradableimplants or pumps), which can be based on, for example, drug diffusionsystems, electrochemical systems, electromechanical systems, osmoticpumps, electrodiffusion systems, electroosmosis systems, vapor pressurepumps, electrolytic pumps, effervescent pumps, piezoelectric pumps,erosion-based systems, diffusive systems and the like.

[0011] The invention further provides methods of treating pain in asubject, comprising delivering from a drug delivery device a fentanyl orfentanyl congener formulation of the invention to a site in the body ofthe subject. Delivery of the formulation is generally continuous, andcan be for a pre-selected administration period ranging from severalhours, one to several weeks, one to several months, up to one or moreyears.

[0012] Pain amenable to alleviation includes all types of acute orchronic pain, e.g., cancer pain, chronic inflammatory disease pain,neuropathic pain, post-operative pain, iatrogenic pain, complex regionalpain syndrome, failed-back pain, soft tissue pain, joint pain, bonepain, central pain, injury pain, arthritic pain, hereditary disease,infectious disease, headache, causalgia, hyperesthesia, sympatheticdystrophy, phantom limb syndrome, and denervation.

[0013] A primary advantage of the present invention is that very potentand concentrated opioid formulations can be achieved by solubilizingvery potent opioids in a small volume of solvent. This makes it possibleto provide therapeutic amounts of drug to a subject in the case wherethe delivery device is relatively small (e.g., an implantable system),where delivery is required for a relatively long duration, or where higheffective doses of drug are required to achieve the desired therapeuticeffect.

[0014] Thus, it is possible to deliver a consistent amount of drug overan extended period of time without the need to refill or replace thedelivery device, thereby reducing risk of infection and tissue damage,increasing patient compliance, and achieving consistent, accuratedosing.

[0015] A primary advantage of the formulations of the invention is thathigh concentrations of fentanyl or fentanyl congener are achievedwithout substantial precipitation of the drug.

[0016] Another important advantage of the formulations of the presentinvention is that therapeutic amounts of drug (even high doses) can bedelivered to internal tissues of the body at a low volume rate. Forcertain body tissues, e.g., subcutaneous space, low volume delivery canmake the delivered formulation more amenable to absorption by the localtissue, and further minimizes local tissue disturbance, trauma, oredema.

[0017] A further advantage of the formulations of the invention is thatprecipitation of the fentanyl/fentanyl congener does not occur when theformulation comes into contact with aqueous environment, such as bodyfluids. Precipitation of drug is clearly undesirable, since it couldlead to local toxic effects, or clogging of the delivery orifice orelsewhere along the delivery route, resulting in uncontrolled deliveryor complete stoppage of delivery, which would adversely affectconsistency and accuracy of dosing and therefore patient safety. Theformulations of the invention avoid these potential problems.

[0018] These and other objects, advantages, and features of theinvention will become apparent to those persons skilled in the art uponreading the details of the invention as more fully described below.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Before the present invention is described, it is to be understoodthat this invention is not limited to particular embodiments described,as such may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

[0020] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

[0021] It must be noted that as used herein and in the appended claims,the singular forms “a”, “and”, and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a formulation” includes a plurality of such formulations and referenceto “the fentanyl congener” includes reference to one or more fentanylcongeners and equivalents thereof known to those skilled in the art, andso forth.

[0022] The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Definitions

[0023] The terms “drug” and “therapeutic agent,” used interchangeablyherein, are generally meant to refer to fentanyl or a fentanyl congener(e.g., sufentanil, alfentanil, lofentanil, carfentanil, remifentanil,trefentanil, and mirfentanil), as well as formulations comprising one ormore of these compounds. Use of “drug” or the phrase “fentanyl orfentanyl congener” is not meant to be limiting to use of, orformulations comprising, only one of these selected opioid compounds.Furthermore, reference to fentanyl alone or to a selected fentanylcongener alone, e.g., reference to “sufentanil,” is understood to beonly exemplary of the drugs suitable for use in formulations accordingto the invention, and is not meant to be limiting in any way.

[0024] The term “subject” is meant any subject, generally a mammal(e.g., human, canine, feline, equine, bovine, etc.), in which managementof pain is desired.

[0025] The term “therapeutically effective amount” is meant an amount ofa therapeutic agent, or a rate of delivery of a therapeutic agent,effective to facilitate a desired therapeutic effect. The precisedesired therapeutic effect (e.g., the degree of pain relief, and sourceof the pain relieved, etc.) will vary according to the condition to betreated, the formulation to be administered, and a variety of otherfactors that are appreciated by those of ordinary skill in the art. Ingeneral, the method of the invention involves the suppression ormitigation of pain in a subject suffering from pain that may beassociated with any of a variety of identifiable or unidentifiableetiologies.

[0026] The term “pain management” is used here to generally describeregression, suppression, or mitigation of pain, including acute andchronic pain, so as to make the subject more comfortable as determinedby subjective criteria, objective criteria, or both. In general, pain isassessed subjectively by patient report, with the health professionaltaking into consideration the patient's age, cultural background,environment, and other psychologic background factors known to alter aperson's subjective reaction to pain.

[0027] “Delivery site” as used herein is meant to refer to an area ofthe body to which drug is delivered. Such delivery sites include, butare not necessarily limited to, intravenous, intraspinal (e.g.,epidural, subdural, or intrathecal), intracerebral, transdermal, orsubcutaneous sites of delivery and the like. Subcutaneous delivery sitesare of particular interest in the present application. Exemplarysubcutaneous delivery sites include external subcutaneous sites (e.g.,under the skin of the arm, shoulder, neck, back, or leg) and internalsubcutaneous sites within a body cavity (e.g., within the mouth).

[0028] “Drug delivery device” as used herein is meant to refer to anydevice suitable for delivering the formulations for pain managementaccording to the invention. “Drug delivery device” thus encompasses, butis not necessarily limited to, external or implanted dosage forms (e.g.,biodegradable implants or pumps) with any mechanism of action, whichdosage forms can be based on, for example, diffusive, erodible, orconvective systems, e.g., osmotic pumps, biodegradable implants,electrodiffusion systems, electroosmosis systems, electrochemicalsystems, vapor pressure pumps, electrolytic pumps, effervescent pumpspiezoelectric pumps, erosion-based systems, electromechanical systems,diffusive systems, etc.

[0029] “Patterned” or “temporal” as used in the context of drug deliveryis meant delivery of drug in a pattern, generally a substantiallyregular pattern, over a pre-selected period of time (e.g., other than aperiod associated with, for example a bolus injection). “Patterned” or“temporal” drug delivery is meant to encompass delivery of drug at anincreasing, decreasing, substantially constant, or pulsatile, rate orrange of rates (e.g., amount of drug per unit time, or volume of drugformulation for a unit time), and further encompasses delivery that iscontinuous or substantially continuous, or chronic.

[0030] The term “controlled drug release device” or “controlled releasedosage form” is meant to encompass any device wherein the release rate(e.g., rate of timing of release) of a drug or other desired substancecontained therein is controlled by the device or dosage form itself andsubstantially not the environment of use, and that can be adapted foruse in the invention, e.g., a dosage form that provides for controlledrelease of drug and at a rate that is suitable to accomplish delivery ofa therapeutically effective amount of fentanyl or a fentanyl congeneraccording to the invention to a site within the body. The terms “device”and “dosage form” are generally used interchangeably herein.

[0031] The term “sustained release dosage form” is meant to refer to adrug dosage form that is adapted for release of a drug formulation(e.g., an opiod) over a pre-selected period of time rather than at onetime as in a bolus administration (e.g., by injection or oraladministration). Sustained release dosage forms can include dosage formscapable of controlled release or patterned release of a drug.

[0032] “Treatment” as in “treatment of pain” is used herein to encompassboth a decrease in pain severity and/or intensity to provide partial orcomplete relief of pain and/or pain symptoms. The effect may beprophylactic in terms of completely or partially preventing or reducingthe severity of pain.

Overview of the Invention

[0033] The present invention is based on the finding that opioid such asfentanyl and its congeners can be formulated at higher concentrationsthan were previously attained. Controlled delivery of fentanyl or afentanyl congener, e.g., sufentanil, over a prolonged period of time,e.g. weeks or months, from a conveniently sized delivery system, e.g.,an implantable pump, that requires highly concentrated formulations.However, fentanyl and its congeners have very low solubility in aqueousvehicles typically used in formulations of these compounds. An aqueousformulation would thus not provide sufficient drug concentration to meetthe desired dosing requirements for a system with a small drugreservoir, e.g., an implantable system, without the need for frequentre-filling of the drug reservoir or providing a new implant. Inaddition, the highly concentrated formulation of the fentanyl orfentanyl congener must be stable (e.g., at body temperatures in the caseof an implanted system) and must maintain the solubility of the drug asit is delivered to the aqueous environment of the body in order to avoidprecipitation and interference of the function of the delivery system(e.g., by blockage of the delivery orifice or elsewhere along thedelivery pathway in a pump system).

[0034] The present invention provides formulations of fentanyl congenerswhich are characterized in that: (1) they have a fentanyl or fentanylcongener concentration of about 2 to about 10,000 times or greater thanthat of currently commercially available formulations; (2) the fentanylor fentanyl congener does not precipitate out when the formulation comesinto contact with an aqueous environment, e.g., in the body of thesubject being treated; and (3) have good stability, even at bodytemperatures. For example, a formulation of sufentanil in accordancewith the present invention are advantageous over current commerciallyavailable sufentanil injection formulation, which contain only about 50μg/mL sufentanil as the citrate salt in aqueous solution.

Formulations Comprising High Concentrations of Fentanyl or a FentanylCongener

[0035] The invention provides a formulation, particularly apharmaceutical formulation, comprising fentanyl or a fentanyl congener.

[0036] The fentanyl or fentanyl congener is present in the formulationin a concentration substantially higher than conventional formulations,e.g., current commercially available formulations. By “substantiallyhigher,” it is intended that the fentanyl or fentanyl congener ispresent in the formulation in a concentration of at least about 2, atleast about 5, at least about 10, at least about 20, at least about 50,at least about 100, at least about 250, at least about 500, at leastabout 1000, at least about 1500, at least about 2000, at least about2500, at least about 3000, at least about 3500, at least about 4000, atleast about 5000, at least about 6000, at least about 7000, at leastabout 8000, at least about 9000, at least about 10,000 times, orgreater, than the solubility of fentanyl or fentanyl congener in aqueoussolution.

[0037] Formulations of the invention comprise fentanyl or a fentanylcongener in a concentration of at least about 0.1 mg/mL, 0.5 mg/mL, 1mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, 75 mg/mL, 100 mg/mL, 150 mg/mL, 200mg/mL, 225 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL,500 mg/mL, or greater. Formulations of the invention comprising fentanylor fentanyl congener are in solution, e.g., are dissolved in a liquid.

[0038] Pharmaceutical grade organic or inorganic carriers and/ordiluents suitable for systemic delivery can be included in theformulation suitable for delivery according to the invention. Suchphysiologically acceptable carriers are well known in the art. Exemplaryliquid carriers for use in accordance with the present invention can besterile non-aqueous or aqueous solutions which contain no materialsother than the active ingredient. In general, hydrophobic solvents aregenerally preferred due to the lipophilicity of fentanyl and fentanylcongeners. The formulations can optionally further comprise a buffersuch as sodium phosphate at physiological pH value, physiological salineor both (e.g., phosphate-buffered saline). Suitable aqueous carriers mayoptionally further comprise more than one buffer salt, as well as othersalts (such as sodium and potassium chlorides) and/or other solutes.

[0039] In general, fentanyl or fentanyl congeners are present in theformulations of the present invention as a fentanyl base or fentanylcongener base, although a formulation of the invention may comprisefentanyl or a fentanyl congener in a form other than a base form, asdiscussed in more detail below.

[0040] In some embodiments, a formulation comprises fentanyl or afentanyl congener and a low molecular weight (e.g., MW less than about300 g/mol) alcohol. In these embodiments, the fentanyl or fentanylcongener is present in the formulation in a concentration of from about0.5 mg/mL to about 500 mg/mL, from about 1 mg/mL to about 450 mg/mL,from about 50 mg/mL to about 400 mg/mL, from about 75 mg/mL to about 300mg/mL, or from about 100 mg/mL to about 250 mg/mL. Suitable lowmolecular weight alcohols include those which are pharmaceuticallyacceptable, and which preferably comprise an aromatic moiety, and whichare relatively immiscible in water (e.g., less than about 5, less thanabout 4, less than about 3, less than about 2, less than about 1 gramcan dissolve in 25 ml H₂O), including, but not limited to, benzylalcohol, and derivatives thereof. Small amounts of otherpharmaceutically acceptable substances such as other pharmaceuticallyacceptable alcohols, e.g., ethanol, or water, may also be present, and,if present, are present in an amount of less than about 10%, less thanabout 5%, or less than about 1%. In a particular embodiment, theformulation comprises fentanyl or fentanyl congener in 100% benzylalcohol.

[0041] In some embodiments, a formulation comprises fentanyl or afentanyl congener, and a nonionic surfactant, in an alcohol ester, e.g.,an ester of a low molecular weight alcohol as described above. In theseembodiments, the fentanyl or fentanyl congener is present in theformulation in a concentration of from about 0.5 mg/mL to about 500mg/mL, from about 1 mg/mL to about 450 mg/mL, from about 50 mg/mL toabout 300 mg/mL, from about 75 mg/mL to about 275 mg/mL, or from about100 mg/mL to about 250 mg/mL. Suitable alcohol esters include thosewhich are pharmaceutically acceptable, which preferably comprise anaromatic moiety, and which are insoluble in water, including, but notlimited to, benzyl benzoate, and derivatives thereof. Small amounts ofpharmaceutically acceptable substances such as pharmaceuticallyacceptable alcohols or other pharmaceutically acceptable alcohol esters,or water, may also be present, and, if present, are present in an amountof less than about 10%, less than about 5%, or less than about 1%. In aparticular embodiment, the alcohol ester is 100% benzyl benzoate.

[0042] Suitable nonionic surfactants include those which arepharmaceutically acceptable, including but not limited to, polysorbate,e.g., polysorbate 20, polysorbate 40, polysorbate 60; sorbitantrioleate; polyoxyethylene polyoxypropyleneglycol, e.g.,polyoxyethylene(160)glycol, and polyoxypropylene(30)glycol. Othernonionic surfactants which are suitable for use in the formulations ofthe present invention include nonionic surfactants of the fatty acidpolyhydroxy alcohol ester type such as sorbitan monolaurate, monooleate,monostearate or monopalmitate, sorbitan tristearate or trioleate,adducts of polyoxyethylene and fatty acid polyhydroxy alcohol esterssuch as polyoxyethylene sorbitan monolaurate, monooleate, monostearate,monopalmitate, tristearate or trioleate, polyethylene glycol fatty acidesters such as polyoxyethyl stearate, polyethylene glycol 400 stearate,polyethylene glycol 2000 stearate, in particular ethyleneoxide-propylene oxide block copolymers of the Pluronics™ (Wyandotte) orSynperonic™ (ICI). In particular embodiments, the nonionic surfactant ispolysorbate 20, polysorbate 40, polysorbate 60, or sorbitan trioleate,or mixtures of one or more of the foregoing.

[0043] In general, a nonionic surfactant is present in the formulationin a concentration of from about 50 mg/mL to about 200 mg/mL, from about75 mg/mL to about 175 mg/mL, or from about 100 mg/mL to about 150 mg/mL.In a particular embodiment, the nonionic surfactant is present in theformulation at 100 mg/mL.

[0044] The formulations of the present invention are characterized inthat the fentanyl or fentanyl congener is present in a highconcentration, as described above. The fentanyl or fentanyl congener issoluble in the formulation, i.e., little or no fentanyl or fentanylcongener precipitates are present, and further, little or no fentanyl orfentanyl congener precipitates when the formulation comes in contactwith an aqueous environment such as a body fluid. Precipitates offentanyl or fentanyl congeners, when present at all, are present in theformulation at less than about 10%, less than about 7.5%, less thanabout 5%, less than about 2.5%, less than about 1%, or less than about0.1% by weight of the total fentanyl or fentanyl congener present in theformulation. Whether precipitates have formed can be determined usingany method known in the art, including, but not limited to, visualinspection with the unaided eye, or under low (e.g., 10× or 25×)magnification.

[0045] Exemplary additional active ingredients that can be present inthe formulations useful with the invention can include an opioidantagonist (e.g., to further decrease the possibility of addiction ordependence, see, e.g., an exemplary osmotic dosage formulationcomprising an opioid agonist and an opioid antagonist is described inU.S. Pat. No. 5,866,164.

Fentanyl and Fentanyl Congeners

[0046] Fentanyl, congeners of fentanyl, and specific derivatives oranalogs of fentanyl or fentanyl congeners (e.g., other derivatives,particularly 4-anilidopiperidine derivatives, of morphine) arecontemplated for delivery according to the invention, althoughvariations within the scope of the invention will be readily apparent tothe ordinarily skilled artisan upon reading the disclosure providedherein. Exemplary fentanyl congeners include, but are not necessarilylimited to sufentanil, alfentanil, lofenatnil, carfentanil,remifentanil, trefentanil, and mirfentanil.

[0047] The specific fentanyl congener used can vary with a variety offactors, including the therapeutic effect desired to be achieved, thepatient's tolerance and/or previous exposure to opioids, etc. Therelative potency of fentanyl or the fentanyl congener may also beconsidered in selection of the drug to be delivered. For example, therank order of potency of fentanyl and selected fentanyl congenersrelative to morphine is as follows:morphine<alfentanil<fentanyl<sufentanil<lofentanil<carfentanil. Fentanylis 292 times, sufentanil, 4,521 times, lofentanil 5,440 times, andcarfentanil 9,441 times more potent than morphine. For a review of thepharmacokinetics of sufentanil, fentanyl, and other fentanyl congeners,see, e.g., Meert (1996) Pharm. World Sci. 18:1-15; Scholz et al. 1996Clin. Pharmacokinet. 31:275-92.

[0048] Methods for manufacture of fentanyl, sufentanil and otherfentanyl congeners are well known in the art, see, e.g., sufentanil(e.g., U.S. Pat. No. 3,998,834; chemical name:((N-[4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]4-piperidinyl]-N-phenylpropanamide2-hydroxy-1,2,3,-propanetricarboxylate (1:1); C₂₂H₃₀N₂O₂S), fentanyl(e.g., U.S. Pat. No. 3,141,823; chemical name:N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide), alfentanil(e.g., U.S. Pat. No. 4,167,574; chemical name:N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide(C₂₁H₃₂N₆O₃)), lofenatnil (e.g., U.S. Pat. No. 3,998,834; chemical name:3-methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylicacid methyl ester), carfentanil (chemical name:methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate(C₂₄H₃₀N₂O₃)), remifentanil (chemical name:3-[4-methoxycarbonyl-4-[(1-oxopropyl) phenylamino]1-piperidine]propanoicacid), trefentanil (chemical name:N-(1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)-propanamide,and mirfentanil (chemical name:[N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide).

[0049] Fentanyl and fentanyl congeners are discussed in detail in, forexample, Goodman and Gilman's The Pharmacological Basis of Therapeutics,Chapter 23, “Opioid Analgesics and Antagonists”, pp. 521-555 (9^(th) Ed.1996); Baly et al. 1991 Med Res. Rev. 11:403-36 (evolution of the4-anilidopiperidine opioids); and Feldman et al. 1991 J. Med. Chem.34:2202-8 (design, synthesis, and pharmacological evaluation of opioidanalgesics). For additional information on fentanyl and fentanylcongeners, see, e.g., Scholz et al. 1996 Clin. Pharmacokinet. 31:275-92(clinical pharmacokinetics of alfentanil, fentanyl, and sufentanil);Meert 1996 Pharmacy World Sci. 18:1-15 (describing pharmacotherapy ofmorphine, fentanyl, and fentanyl congeners); Lemmens et al. 1995 Anesth.Analg. 80:1206-11 (pharmacokinetics of mirfentanil); Minto et al., 1997Int. Anesthesiol. Clin. 35:49-65 (review of recently developed opioidanalgesics); James 1994 Expert Opin. Invest. Drugs 3:331-40 (discussionof remifentanil); Rosow 1993 Anesthesiology 79:875-6 (discussion ofremifentanil); Glass 1995 Eur. J. Anaesthesiol. Suppl. 10:73-4.(pharmacology of remifentanil); and Lemmens et al. 1994 Clin. Pharmacol.Ther. 56:261-71 (pharmacokinetics of trefentanil)

[0050] Fentanyl or a fentanyl congener can be provided in theformulation as the opioid base and/or the opioid pharmaceuticallyacceptable salt, but is preferably provided in the formulation as theopioid base. The pharmaceutically acceptable salt embraces the inorganicand the organic salt. Representative salts include a member selectedfrom the group consisting of hydrobromide, hydrochloride, mucate,citrate, succinate, n-oxide, sulfate, malonate, acetate, phosphatedibasic, phosphate monobasic, acetate trihydrate,bi(heptafluorobutyrate), maleate, bi(methylcarbamate),bi(pentafluoropropionate), mesylate, bi(pyridine-3-carboxylate),bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate and sulfatepentahydrate. Where the drug formulation comprises sufentanil, use ofthe sufentanil base is specifically contemplated for use.

Dosage Forms Useful in the Methods of the Invention

[0051] Any of a variety of dosage forms can be used in conjunction witha formulation of the present invention. Delivery methods and dosageforms suitable for use with the formulations of the present inventioncan take advantage of any of a variety of drug release mechanisms.

[0052] In general, the dosage forms suitable for use in the inventionare adapted for retaining a quantity of drug formulation (e.g.,contained in a drug reservoir or solubilized, suspended or integratedinto a vehicle, substrate or matrix such as a polymer, binding solid,etc.) sufficient for treatment for a pre-selected period. In general thedosage forms for use with the present invention are adapted forsustained release of the formulation. Exemplary dosage forms includedrug delivery devices (e.g., drug pumps), bioerodable implants,sustained release injectables (e.g., injectable high viscousformulations, gels including hydrogels such as collagen hydrogels),microparticulate suspensions, microsphere suspensions, liposomeformulations, micelle formulations, oil suspensions (includingemulsions), and encapsulated particulate suspensions. Drug deliverydosage forms that may be suitable for use with the present invention aredescribed in Encyclopedia of Controlled Drug Delivery (1999), EdithMathiowitz (Ed.), John Wiley & Sons, Inc. The dosage form can beselected from, for example, any of a variety of conventional drugrelease devices that are conventionally used as an external element(e.g., an external pump) or implanted element of a drug delivery system.

[0053] In some embodiments, the dosage form (also referred to herein asa delivery device) is one that is adapted for delivery of fentanyl orfentanyl congener over extended periods of time. Such delivery devicesmay be adapted for administration of fentanyl or fentanyl congener forseveral hours (e.g. 2 hours, 12 hours, or 24 hours to 48 hours or more),to several days (e.g., 2 to 5 days or more, from about 100 days ormore), to several months or years. In some of these embodiments, thedevice is adapted for delivery for a period ranging from about 1 monthto about 12 months or more. The drug delivery device may be one that isadapted to administer fentanyl or fentanyl congener to an individual fora period of, e.g., from about 2 hours to about 72 hours, from about 4hours to about 36 hours, from about 12 hours to about 24 hours; fromabout 2 days to about 30 days, from about 5 days to about 20 days, fromabout 7 days to about 100 days or more, from about 10 days to about 50days; from about 1 week to about 4 weeks; from about 1 month to about 24months or more, from about 2 months to about 12 months, from about 3months to about 9 months; or other ranges of time, including incrementalranges, within these ranges, as needed.

[0054] Release of drug from the dosage form, particularly controlledrelease of drug, can be accomplished in any of a variety of waysaccording to methods well known in the art, e.g., by solubilization orsuspension of drug in a vehicle or incorporation of drug into a polymerthat provides for substantially controlled diffusion of drug from withinthe polymer, incorporation of drug in a biodegradable polymer, providingfor delivery of drug from an osmotically-driven device, etc. Where thedrug delivery device comprises a drug delivery catheter, drug can bedelivered through the drug delivery catheter to the delivery site as aresult of capillary action, as a result of pressure generated from thedrug device, by diffusion, by electrodiffusion or by electroosmosisthrough the device and/or the catheter.

[0055] In general, the dosage form is adapted to carry the drugformulation in such quantities and concentration as therapeuticallyrequired for treatment over the pre-selected period, and must providesufficient protection to the formulation from degradation by bodyprocesses for the duration of treatment. For example, the dosage formcan be surrounded by an exterior made of a material that has propertiesto protect against degradation from metabolic processes and the risk of,e.g., leakage, cracking, breakage, or distortion. This can preventexpelling of the dosage form contents in an uncontrolled manner understresses it would be subjected to during use, e.g., due to physicalforces exerted upon the drug release device as a result of movement bythe subject or for example, in convective drug delivery devices,physical forces associated with pressure generated within the reservoir.The drug reservoir or other means for holding or containing the drugmust also be of such material as to avoid unintended reactions with theactive agent formulation, and is preferably biocompatible (e.g., wherethe dosage form is implanted, it is substantially non-reactive withrespect to a subject's body or body fluids).

[0056] Suitable materials for the reservoir or drug holding means foruse in the delivery devices of the invention are well known in the art.For example, the reservoir material may comprise a non-reactive polymeror a biocompatible metal or alloy. Suitable polymers include, but arenot necessarily limited to, acrylonitrile polymers such asacrylonitrile-butadiene-styrene polymer, and the like; halogenatedpolymers such as polytetrafluoroethylene, polyurethane,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyethylene vinylacetate (EVA), polyimide;polysulfone; polycarbonate; polyethylene; polypropylene;polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; cellulosicpolymers; and the like. Further exemplary polymers are described in TheHandbook of Common Polymers, Scott and Roff, CRC Press, Cleveland RubberCo., Cleveland, Ohio.

[0057] Metallic materials suitable for use in the reservoir of the drugdelivery devices include stainless steel, titanium, platinum, tantalum,gold and their alloys; gold-plated ferrous alloys; platinum-platedtitanium, stainless steel, tantalum, gold and their alloys as well asother ferrous alloys; cobalt-chromium alloys; and titaniumnitride-coated stainless steel, titanium, platinum, tantalum, gold, andtheir alloys.

[0058] Exemplary materials for use in polymeric matrices include, butare not necessarily limited to, biocompatible polymers, includingbiostable polymers and biodegradable polymers. Exemplary biostablepolymers include, but are not necessarily limited to silicone,polyurethane, polyether urethane, polyether urethane urea, polyamide,polyacetal, polyester, poly ethylene-chlorotrifluoroethylene,polytetrafluoroethylene (PTFE or “Teflon™”), styrene butadiene rubber,polyethylene, polypropylene, polyphenylene oxide-polystyrene,poly-a-chloro-p-xylene, polymethylpentene, polysulfone and other relatedbiostable polymers. Exemplary biodegradable polymers include, but arenot necessarily limited to, polyanhydrides, cyclodestrans,polylactic-glycolic acid, polyorthoesters, n-vinyl alcohol, polyethyleneoxide/polyethylene terephthalate, polyglycolic acid, polylactic acid,sucrose acetate isobutyrate, and other related bioabsorbable polymers.

[0059] Where the drug formulation is stored in a reservoir comprisingmetal or a metal alloy, particularly titanium or a titanium alloy havinggreater than 60%, often greater than 85% titanium is preferred for themost size-critical applications, for high payload capability and forlong duration applications and for those applications where theformulation is sensitive to body chemistry at the implantation site orwhere the body is sensitive to the formulation. Most preferably, thedrug delivery devices are designed for storage with drug at roomtemperature or higher.

[0060] Drug release devices suitable for use in the invention may bebased on any of a variety of modes of operation. For example, the drugrelease device can be based upon a diffusive system, a convectivesystem, or an erodible system (e.g., an erosion-based system). Forexample, the drug release device can be an osmotic pump, anelectroosmotic pump, a vapor pressure pump, or osmotic bursting matrix,e.g., where the drug is incorporated into a polymer and the polymerprovides for release of drug formulation concomitant with degradation ofa drug-impregnated polymeric material (e.g., a biodegradable,drug-impregnated polymeric material). In other embodiments, the drugrelease device is based upon an electrodiffusion system, an electrolyticpump, an effervescent pump, a piezoelectric pump, a hydrolytic system,etc.

[0061] Drug release devices based upon a mechanical or electromechanicalinfusion pump, can also be suitable for use with the present invention.Examples of such devices include those described in, for example, U.S.Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and thelike. In general, the present methods of drug delivery can beaccomplished using any of a variety of refillable, non-exchangeable pumpsystems. Pumps and other convective systems are generally preferred dueto their generally more consistent, controlled release over time.Osmotic pumps are particularly preferred due to their combinedadvantages of more consistent controlled release and relatively smallsize. Exemplary osmotically-driven devices suitable for use in theinvention include, but are not necessarily limited to, those describedin U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790;3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203;4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845;5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693;5,728,396; 5,985,305; and the like.

[0062] In one embodiment, the drug release device is a controlled drugrelease device in the form of an osmotically-driven device. Preferredosmotically-driven drug release systems are those that can provide forrelease of agent in a range of rates of from about 0.01 mg/hr to about1000 mg/hr, and which can be delivered at a volume rate range of, forexample, from about 0.001 ml/day to about 100 ml/day (i.e., from about0.0004 ml/hr to about 4 ml/hr), from about 0.04 ml/day to about 10ml/day, from about 0.2 ml/day to about 5 ml/day, from about 0.5 ml/dayto about 1 ml/day In general, in the present invention, the drug releasesystem is selected to provide for delivery of a bisphosphonate at a rateof from about 0.001 ml/day (1 ml/day) to at least about 500 ml/day orabout 1 ml/day (i.e., from about 0.04 ml/hr to about 21 ml/hr to about42 ml/hr), from about 2 ml/day to about 250 ml/day to 500 ml/day, fromabout 4 ml/day to about 100 ml/day, from about 5 ml/day to about 50ml/day to 250 ml/day.

[0063] In an embodiment, the sustained release dosage form is adepot-type injectable, see e.g., U.S. Pat. Nos. 6,183,781; 6,174,547;6,156,331; 6,143,314; 6,130,200; 6,120,789; 6,051,558; 5,989,463;5,968,542; 5,912,015; 5,747,058; 5,702,716; 5,654,008; and 5,650,173.

[0064] In one embodiment of particular interest, the volume/timedelivery rate is substantially constant (e.g., delivery is generally ata rate ± about 5% to 10% of the cited volume over the cited timeperiod). In one embodiment, the drug release device is a continuous drugrelease device in the form of an osmotically-driven device. Preferredosmotically-driven drug release systems are those that can provide forrelease of drug in a range of rates of from about 0.1 mg/hr to about1000 mg/hr, and which can be delivered at a volume rate of from about0.25 ml/day to about 100 ml/day (i.e., from about 0.0004 ml/hr to about4 ml/hr), from about 0.04 ml/day to about 10 ml/day, and can be fromabout 0.2 ml/day to about 5 ml/day, or from about 0.5 ml/day to about 1ml/day. In one embodiment, the volume/time delivery rate issubstantially constant (e.g., delivery is generally at a rate ± about 5%to 10% of the cited volume over the cited time period).

[0065] The invention features methods for management of pain by deliveryof a formulation of the invention. In one embodiment, the drugformulation of the invention is delivered in a substantially continuousfashion. While the formulations of the invention can be delivered to anyof a variety of delivery sites, the formulations can find particular usein delivery of fentanyl or a fentanyl congener (particularly sufentanil)to a subcutaneous site. Methods of subcutaneous delivery fentanyl or afentanyl congener (particularly sufentanil) are described in the U.S.regular utility application entitled “Devices and Methods for PainManagement,” U.S. application Ser. No. 09/522,535 filed on Aug. 3, 2000,which application is specifically incorporated herein by reference.

Methods of Alleviating Pain in a Subject Using a Formulation of theInvention

[0066] Although the formulations of the present invention can be usedfor a variety of therapeutic purposes for which opioids are suitable,the formulations of the invention are particularly useful foralleviating pain in a subject suffering from pain, such methodscomprising administering to a subject suffering from pain a formulationof the present invention. In particular embodiments, the formulation isadministered using a drug delivery device suitable for long-termdelivery, e.g., a drug delivery device as described above. In general,the methods comprise delivering from a drug delivery device aformulation comprising fentanyl or fentanyl congener in an amounteffective to alleviate pain in the subject.

[0067] Subjects suffering from or susceptible to pain can receivealleviation of pain according to the method of the invention for anydesired period of time. In general, administration of fentanyl orfentanyl congener according to the invention can be sustained forseveral hours (e.g., 2 hours, 12 hours, or 24 hours to 48 hours ormore), to several days (e.g., 2 to 5 days or more), to several months oryears. Typically, delivery can be continued for a period ranging fromabout 1 month to about 12 months or more. The fentanyl or fentanylcongener may be administered to an individual for a period of, forexample, from about 2 hours to about 72 hours, from about 4 hours toabout 36 hours, from about 12 hours to about 24 hours, from about 2 daysto about 30 days, from about 5 days to about 20 days, from about 7 daysto about 100 days or more, from about 10 days to about 50 days, fromabout 1 week to about 4 weeks, from about 1 month to about 24 months,from about 2 months to about 12 months, or from about 3 months to about9 months, or other ranges or time, including incremental ranges withthese ranges, as needed. This extended period of opioid delivery is madepossible by the high concentration of opioids present in theformulations of the invention. In particular embodiments, the fentanylor fentanyl congener is delivered to the subject without the need forre-accessing the device and/or without the need for re-filling thedevice. In these embodiments, high-concentration formulations offentanyl or fentanyl congener are of particular interest.

[0068] Preferably, delivery of fentanyl or fentanyl congener issubstantially continuous, e.g., substantially uninterrupted for apre-selected period of drug delivery, and more preferably at asubstantially constant, pre-selected rate or range of rates (e.g.,amount of drug per unit time, or volume of drug formulation for a unittime). The drug is preferably delivered at a volume rate of from about0.01 μl/day to about 2 ml/day, preferably about 0.04 μl/day to about 1ml/day, generally about 0.2 μl/day to about 0.5 ml/day, typically fromabout 2.0 μl/day to about 0.25 ml/day.

[0069] In one embodiment, a drug delivery device provides forsubstantially continuous delivery of drug at a preselected rate. Forexample, for subcutaneous delivery of sufentanil, the drug can bedelivered at a rate of from about 0.1 μg/hr to about 200 μg/hr, fromabout 0.25 μg/hr to about 100 μg/hour, usually between about 3 μg/hr toabout 85 μg/hr, and typically between about 5 μg/hr to about 100 μg/hr.In a specific exemplary embodiment, sufentanil is delivered at a rate offrom about 0.01 μg/hour, about 0.1 μg/hour, about 0.25 μg/hour, or about1 μg/hour, generally up to about 200 μg/hour. Appropriate amounts offentanyl or fentanyl congener can be readily determined by theordinarily skilled artisan based upon, for example, the relative potencyof these drugs. The actual dose of drug delivered will vary with avariety of factors such as the potency and other properties of theselected drug used (e.g., lipophilicity, etc.).

[0070] Substantially continuous delivery of fentanyl or fentanylcongener (e.g., by infusion, diffusion, etc.) according to the inventioncan be accomplished using, for example, a drug delivery device in theform of an external or implantable pump. Use of such drug deliverydevices provides at least the following additional advantages: (1) thetherapeutic analgesic effect of the drug(s) is essentially continuous;(2) drug is delivered to the subject in a smooth and consistent fashion(e.g., the bolus effect is substantially avoided both at the initiationof therapy and throughout the pre-selected period of therapy); (3) thepotential for misuse or abuse of the opioid is substantially diminished(e.g., the patient does not have ready access to a surplus of sufentanilthat is not contained in the delivery device); (4) the risk ofoverdosing and resulting toxic reactions are decreased (e.g., risk ofoverdose due to patient or health professional error duringadministration is avoided); (5) patient compliance is increased (e.g.,the device ensures that drug is continually administered throughout thepre-selected therapeutic period); and (6) safe delivery with a widerange of delivery rates. Drug delivery devices suitable for use in thepresent invention are described in further detail above. Routes ofdelivery contemplated by the invention include, but are not necessarilylimited to, parenteral routes (e.g., subcutaneous, intravenous,intramuscular, intraspinal, and the like). Subcutaneous delivery is adelivery route of particular interest.

Pain Susceptible to Management According to the Methods of the Invention

[0071] In general, administration of fentanyl or a fentanyl congenerformulation according to the invention can be used to facilitatemanagement of pain that is associated with any of a wide variety ofdisorders, conditions, or diseases. Causes of pain may be identifiableor unidentifiable. Where identifiable, the origin of pain may be, forexample, of malignant, non-malignant, infectious, non-infectious, orautoimmune origin. Of particular interest is the management of painassociated with disorders, diseases, or conditions that requirelong-term therapy, e.g., chronic and/or persistent diseases orconditions for which therapy involves treatment over a period of severaldays (e.g., about 3 days to 10 days), to several weeks (e.g., about 3 or4 weeks to 6 weeks), to several months or years, up to including theremaining lifetime of the subject. Subjects who are not presentlysuffering from a disease or condition, but who are susceptible to suchmay also benefit from prophylactic pain management using the devices andmethods of the invention, e.g., prior to traumatic surgery. Painamenable to therapy according to the invention may involve prolongedepisodes of pain alternating with pain-free intervals, or substantiallyunremitting pain that varies in severity.

[0072] In general, pain can be somatogenic, neurogenic, or psychogenic.Somatogenic pain can be muscular or skeletal (i.e., osteoarthritis,lumbosacral back pain, posttraumatic, myofascial), visceral (i.e.,chronic pancreatitis, ulcer, irritable bowel), ischemic (i.e.,arteriosclerosis obliterans), or related to the progression of cancer(e.g., malignant or non-malignant). Neurogenic pain can be due toposttraumatic and postoperative neuralgia, can be related toneuropathies (i.e., diabetes, toxicity, etc.), and can be related tonerve entrapment, facial neuralgia, perineal neuralgia, postamputation,thalamic, causalgia, and reflex sympathetic dystrophy.

[0073] Specific examples of conditions, diseases, disorders, and originsof pain amenable to management according to the present inventioninclude, but are not necessarily limited to, cancer pain (e.g.,metastatic or non-metastatic cancer), chronic inflammatory disease pain,neuropathic pain, post-operative pain, iatrogenic pain (e.g., painfollowing invasive procedures or high dose radiation therapy, e.g.,involving scar tissue formation resulting in a debilitating compromiseof freedom of motion and substantial chronic pain), complex regionalpain syndromes, failed-back pain (chronic back pain), soft tissue pain,joints and bone pain, central pain, injury (e.g., debilitating injuries,e.g., paraplegia, quadriplegia, etc., as well as non-debilitating injury(e.g., to back, neck, spine, joints, legs, arms, hands, feet, etc.)),arthritic pain (e.g., rheumatoid arthritis, osteoarthritis, arthriticsymptoms of unknown etiology, etc.), hereditary disease (e.g., sicklecell anemia), infectious disease and resulting syndromes (e.g., Lymedisease, AIDS, etc.), chronic headaches (e.g., migranes), causalgia,hyperesthesia, sympathetic dystrophy, phantom limb syndrome,denervation, and the like. Pain can be associated with any portion(s) ofthe body, e.g.,the musculoskeletal system, visceral organs, skin,nervous system, etc.

[0074] Cancer pain is an example of one broad category of pain that canbe alleviated according to the methods of the invention. One of theunderlying causes of cancer pain is the severe local stretching oftissues by the neoplastic lesion. For example, as the cancer cellsproliferate in an unrestricted manner, the tissues in the local regionof cancer cell proliferation are subjected to mechanical stress requiredto displace tissue and accommodate the increased volume occupied by thetumor mass. When the tumor burden is confined to a small enclosedcompartment, such as the marrow of a bone, the resulting pressure canresult in severe pain. Another cause of pain can result from theaggressive therapies used to combat the patient's cancer, e.g.,radiation therapy, chemotherapy, etc. Such cancer therapies can involvelocalized or widespread tissue damage, resulting in pain.

[0075] Pain associated with any type of malignant or non-malignantcancer is amenable to alleviation according to the invention. Specificexamples of cancers that can be associated with pain (due to the natureof the cancer itself or therapy to treat the cancer) include, but arenot necessarily limited to lung cancer, bladder cancer, melanoma, bonecancer, multiple myeloma, brain cancer, non-Hodgkins lymphoma, breastcancer, oral cancers, cervical cancer, ovarian cancer, colon cancer,rectal cancer, pancreatic cancer, dysplastic nevi, endocrine cancer,prostate cancer, head and neck cancers, sarcoma, Hodgkins disease, skincancer, kidney cancer, stomach cancer, leukemia, testicular cancer,liver cancer, uterine cancer, and aplastic anemia. Certain types ofneuropathic pain can also be amenable to treatment according to theinvention.

[0076] Chronic back pain, which is also amenable to management using themethods of the invention, is another broad category of pain that can bealleviated by application of the methods of the invention. Chronic backpain is generally due to one or more of the following six causes: (i)stress on intervertebral facet joints, caused by slippage, arthritis,wedging, or scoliosis; (ii) radiculopathy, the mechanical compression ofthe nerve root due to bulging discs or tumors; (iii) tendonitis ortendon sprain; (iv) muscle spasm or muscle sprain; (v) ischemia, a localinsufficiency in circulatory flow; and (vi) neuropathy, damage tonervous tissue of metabolic etiology or arising from cord tumors orcentral nervous system disease.

[0077] The methods of the invention can be used to manage pain inpatients who are opioid naive or who are no longer opioid naive.Exemplary opioid naive patients are those who have not receivedlong-term opioid therapy for pain management. Exemplary non-opioid naivepatients are those who have received short-term or long-term opioidtherapy and have developed tolerance, dependence, or other undesirableside effect. For example, patients who have intractable adverse sideeffects with oral, intravenous, or intrathecal morphine, transdermalfentanyl patches, or other conventional methods and devices of opioiddelivery can achieve good analgesia and maintain favorable side-effectsprofiles with delivery of fentanyl or a fentanyl congener whenadministered in the dose ranges and/or low volume rates described above.

EXAMPLES

[0078] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow to make and use the present invention, and are not intended to limitthe scope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric.

Example 1 Formulations Comprising Sufentanil in Benzyl Alcohol

[0079] 397 mg/mL Formulation

[0080] 3.97 g of sufentanil base were weighed out and added to a portionof benzyl alcohol. The drug was dissolved in the benzyl alcohol bystirring with a magnetic stirrer. When the resultant preparation wasclear, additional benzyl alcohol was added to obtain 10 mL offormulation. The resultant formulation concentration was 397 mg/mL.

[0081] 310 mg/mL Formulation

[0082] 3.1 g of sufentanil base were weighed out and added to a portionof benzyl alcohol. The drug was dissolved in the benzyl alcohol bystirring with a magnetic stirrer. When the resultant preparation wasclear, additional benzyl alcohol was added to obtain 10 mL offormulation. The resultant formulation concentration was 310 mg/mL.

Example 2 Formulations Comprising Sufentanil in Benzyl Benzoate

[0083] 248 mg/mL Formulation

[0084] The vehicle solution was prepared by adding 3 mL of polysorbate20 to sufficient benzyl benzoate to make 30 mL of solution. The mixturewas stirred using a magnetic stirrer until the polysorbate 20 wasdispersed in the benzyl benzoate. 7.44 g sufentanil base was weighed outand added to a portion of the vehicle solution. The drug was dissolvedby sonicating the flask in a sonication bath. When the resultantpreparation was clear, an additional quantity of the vehicle was addedto obtain 30 mL of formulation. The resultant formulation concentrationwas 248 mg/mL.

[0085] 77 mg/mL Formulation

[0086] The vehicle solution was prepared by adding 3 mL of polysorbate20 to sufficient benzyl benzoate to make 30 mL of solution. The mixturewas stirred using a magnetic stirrer until the polysorbate 20 wasdispersed in the benzyl benzoate. 2.322 g sufentanil base was weighedout and added to a portion of the vehicle solution. The drug wasdissolved by sonicating the flask in a sonication bath. When theresultant preparation was clear, an additional quantity of the vehiclewas added to obtain 30 mL of formulation. The resultant formulationconcentration was 77.4 mg/mL.

[0087] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A pharmaceutical formulation comprising fentanyl or a fentanyl congener and a non-aqueous carrier, wherein the fentanyl or fentanyl congener is present in the formulation at a concentration of at least about 500 μg/mL.
 2. The pharmaceutical formulation according to claim 1, wherein the nonaqueous carrier is a lower molecular weight alcohol comprising an aromatic moiety.
 3. The pharmaceutical formulation according to claim 2, wherein the alcohol is benzyl alcohol.
 4. The pharmaceutical formulation according to claim 1, wherein the nonaqueous carrier comprises a non-ionic surfactant and an alcohol ester.
 5. The pharmaceutical formulation according to claim 4, wherein the non-ionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 80, and sorbitan trioleate.
 6. The pharmaceutical formulation according to claim 4, wherein the alcohol is benzyl alcohol.
 7. A pharmaceutical formulation comprising fentanyl or a fentanyl congener in a concentration of from about 0.5 mg/mL to about 500 mg/mL in a lower molecular weight alcohol which comprises an aromatic moiety.
 8. The pharmaceutical formulation of claim 7, comprising fentanyl or fentanyl congener in a concentration of from about 50 mg/mL to about 400 mg/mL.
 9. The pharmaceutical formulation of claim 7, wherein the fentanyl congener is sufentanil.
 10. The pharmaceutical formulation of claim 7, wherein the lower molecular weight alcohol is benzyl alcohol.
 11. The pharmaceutical formulation of claim 7, wherein the fentanyl or a fentanyl congener is present in the formulation as a fentanyl base or a fentanyl congener base.
 12. A pharmaceutical formulation comprising fentanyl or a fentanyl congener in a concentration from about 0.5 mg/mL to about 500 mg/mL, and a nonionic surfactant in a concentration of from about 50 mg/mL to about 200 mg/mL, in an alcohol ester which comprises an aromatic moiety.
 13. The pharmaceutical formulation of claim 12, comprising fentanyl or fentanyl congener in a concentration of from about 50 mg/mL to about 250 mg/mL.
 14. The pharmaceutical formulation of claim 12, wherein the fentanyl congener is sufentanil.
 15. The pharmaceutical formulation of claim 12, wherein the nonionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 80, and sorbitan trioleate.
 16. The pharmaceutical formulation of claim 12, wherein the alcohol ester is benzyl benzoate.
 17. The pharmaceutical formulation of claim 12, wherein the fentanyl or fentanyl congener is present in the formulation as a fentanyl base or a fentanyl congener base.
 18. A dosage form comprising a formulation according to claims 1, 7 or
 12. 19. A method of treating pain in a subject suffering from pain, comprising administering to a subject suffering from pain a formulation according to claims 1, 7 or 12 in an amount effective to alleviate pain in the subject.
 20. A pharmaceutical formulation comprising sufentanil and a non-aqueous diluent, wherein sulfentanil is present in the formulation in a concentration greater than about 500 μg/mL.
 21. The pharmaceutical formulation of claim 20, wherein the formulation comprises a lower molecular weight alcohol comprising an aromatic moiety.
 22. The pharmaceutical formulation of claim 21, wherein the lower molecular weight alcohol is benzyl alcohol.
 23. The pharmaceutical formulation of claim 20, wherein the formulation comprises a nonionic surfactant in a concentration of from about 50 mg/mL to about 200 mg/mL, and an alcohol ester which comprises an aromatic moiety.
 24. The pharmaceutical formulation of claim 23, wherein the alcohol ester is benzyl benzoate and wherein the nonionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 80, and sorbitan trioleate.
 25. A drug dosage form comprising a formulation according claim
 20. 26. A method of treating pain in a subject suffering from pain, comprising administering to a subject suffering from pain a formulation according to claim 20, thereby alleviating pain in the subject. 